3-186743088-T-C

Position:

• chr3-186743088-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001102416.3(KNG1):​c.*757T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 325,314 control chromosomes in the GnomAD database, including 29,240 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14048 hom., cov: 31)
  • Exomes 𝑓: 0.41 (15192 hom.)
• Consequence: KNG1 NM_001102416.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343

Genes affected

KNG1 (HGNC:6383): (kininogen 1) This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.*757T>C		3_prime_UTR_variant	10/10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.1204-617T>C		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.1096-617T>C		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.*757T>C		3_prime_UTR_variant	10/10		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64680 AN: 151790 Hom.: 14031 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.426

GnomAD4 exome AF: 0.414 AC: 71836 AN: 173406 Hom.: 15192 Cov.: 5 AF XY: 0.417 AC XY: 34644 AN XY: 83170

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.362

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.394

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.382

Gnomad4 NFE exome AF: 0.408

Gnomad4 OTH exome AF: 0.432

GnomAD4 genome AF: 0.426 AC: 64726 AN: 151908 Hom.: 14048 Cov.: 31 AF XY: 0.427 AC XY: 31697 AN XY: 74222

Gnomad4 AFR AF: 0.430

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.427

Alfa AF: 0.420 Hom.: 13483

Bravo AF: 0.416

Asia WGS AF: 0.512 AC: 1784 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5030091; hg19: chr3-186460877;